Matrix metalloproteinases, tumor necrosis factor and multiple sclerosis: an overview
Section snippets
Metalloproteinases
The metalloproteinases (MPs) are a large family of enzymes which contain a zinc atom in the active site of their catalytic domain (Rawlings and Barrett, 1995). The matrix metalloproteinases (MMPs) are a distinct sub-group of MPs which includes the collagenases, gelatinases, stromelysins, membrane-type metalloproteinases, matrilysin and metalloelastase (Birkedal-Hansen et al., 1993). The MMPs generally have broad, but not necessarily overlapping, substrate specificities. Classically MMP
Metalloproteinase inhibitors
MMPs have been a target for the pharmaceutical industry for many years and a number of substrate-based pseudopeptide inhibitors have been described (reviewed by Beckett et al., 1996). MMP inhibitors have shown efficacy in models of cancer, acute and chronic inflammatory diseases. The most advanced clinical studies to date have been in corneal ulceration with the Glycomed compound GalardinTM (given by injection), in malignant pleural effusion and ascites with the British Biotech compound
Relationship of MMPs to the cytokine convertase/sheddase
It is not yet clear to what extent MMPs participate in the release of TNF or of other shed membrane molecules in vivo. There is emerging evidence that the shedding reaction can be mediated by novel metalloproteinases. Although we have shown that many of our MMP inhibitors also prevent the cellular processing of pro-TNF (Gearing et al., 1994), detailed analysis of the inhibitory potency of different compounds suggest that the TNF converting enzyme may be pharmacologically distinct from the
Demyelinating neuroinflammatory disease: the case for treatment with a TMI
Multiple sclerosis is a chronic disabling disease of the central nervous system (CNS). The disease is characterised by the presence of demyelinated plaques or lesions, which early in their development have a disrupted blood brain barrier causing leakage of plasma proteins (Calder et al., 1989). These plaques contain inflammatory cells (T lymphocytes and monocytes) in addition to activated glial cells. It is thought that an initial influx of inflammatory cells drives the subsequent development
Summary
MMPs are potent mediators of tissue destruction in autoimmune disease. MMPs also contribute to the release or shedding of cell surface molecules such as TNF-α. There is considerable evidence that MMPs are expressed in the lesions of MS where they contribute to leucocyte invasion, BBB breakdown, myelin destruction and TNF release. Compounds which inhibit MMP activity and TNF release are active in animal models of MS. In view of this, clinical trials of a broad spectrum MMP inhibitor should be
Acknowledgements
I would like to thank the British Biotech MMP team and Dr. V.H. Perry of the Department of Pharmacology, University of Oxford for their contributions to this work.
References (95)
- Abramson, S. et al. (1995) Characterization of rat uterine matrilysin and its cDNA. J. Biol. Chem., 270,...
- Aimes, R. and Quigley, J. (1995) Matrix metalloproteinase-2 is an interstitial collagenase: Inhibitor-free enzyme...
- Apodaca, G. et al. (1990) Expression of metalloproteinases and metalloproteinase inhibitors by fetal astrocytes and...
- Arribas, J. et al. (1996) Diverse cell surface protein ectodomains are shed by a system sensitive to metalloprotease...
- Baker, D. et al. (1994) Control of established experimental allergic encephalomyelitis by inhibition of tumor necrosis...
- Banda, M. et al. (1987) Interaction of mouse macrophage elastase with native and oxidised human alpha 1-proteinase...
- Beckett, R.P. et al. (1996) Recent advances in matrix metalloproteinase inhibitor research. DDT 1,...
- Benvenuto, R. et al. (1991) Tumour necrosis factor alpha synthesis by cerebrospinal fluid-derived T cell clones from...
- Birkedal-Hansen, H. et al. (1993) Matrix metalloproteinases: A review. Crit. Rev. Oral Biol. Med. 4,...
- Calder, V. et al. (1989) MS: A localized immune disease of the central nervous system. Immunol. Today 10,...
Cited by (249)
ZFP403, a novel tumor suppressor, inhibits the proliferation and metastasis in ovarian cancer
2017, Gynecologic OncologyCitation Excerpt :Matrix metalloproteinases (MMPs) are a family of structurally and functionally related zinc-dependent enzymes that closely correlated with tumor metastasis, invasion and tumor growth. The possible mechanisms are that they participate in proteolytic degradation of ECM components, remodification of the ECM during angiogenesis and possibly regulation of tumor cell growth itself [19–21,37]. Among all the different types of MMPs, MMP-2 (72 kDa) and MMP-9 (92 kDa) have been involved extensively in facilitating malignant tumor metastasis.
Development of temporomandibular joint arthritis: The use of animal models
2017, Joint Bone SpineAge-related differences in the neuromuscular performance of fatigue-provoking exercise under severe whole-body hyperthermia conditions
2023, Scandinavian Journal of Medicine and Science in SportsADAM10 and ADAM17, Major Regulators of Chronic Kidney Disease Induced Atherosclerosis?
2023, International Journal of Molecular SciencesThe Translatability of Multiple Sclerosis Animal Models for Biomarkers Discovery and Their Clinical Use
2022, International Journal of Molecular SciencesMatrix Metalloproteinases: From Molecular Mechanisms to Physiology, Pathophysiology, and Pharmacology<sup>S</sup>
2022, Pharmacological Reviews